New Orleans, LA and Chapel Hill, NC – April 4, 2011 – Cardioxyl Pharmaceuticals, Inc. announced today that it is presenting two abstracts from studies of its lead clinical candidate, CXL-1020, at the American College of Cardiology’s (ACC) 60th Annual Scientific Session & Expo in New Orleans, Louisiana. Preclinical results highlighted in the first abstract demonstrate CXL-1020’s ability to work independently from other heart failure therapies, furthering important insights into the cellular mechanism of action of nitroxyl donors. Clinical results presented in the second abstract demonstrate, for the first time, CXL-1020’s safety and tolerability in people who have stable congestive heart failure (CHF), a good predictor of safety in people with acute decompensated heart failure (ADHF).
“Today’s research findings provide additional support for the unique mechanism of CXL-1020 and for its strong safety profile and tolerability in patients with stable CHF,” said Chris Kroeger, M.D., President and Chief Executive Officer. “We are currently enrolling a Phase IIa clinical trial to further define safety, tolerability and dosing for CXL-1020 in patients with ADHF, bringing us closer to making this treatment a reality for the millions who suffer from this disease.”
Following are the details of the data presented at ACC Poster Sessions:
CXL-1020, a Novel HNO Donor, Decreases Myocardial Loading and Enhances Load-Independent Lusitropy and Inotropy via a Beta-AR/ACE Independent Mechanism. Monday, April 4, 2011; 1:45 p.m. – 4:45 p.m., Ernest N. Morial Convention Center, Hall F; Poster Board #21
In this preclinical study, Cardioxyl and QTest Labs researchers compared the hemodynamic profile of CXL-1020 with the vasodilator, sodium nitroprusside (SNP). The results show that under conditions of matched reduction of systolic pressure, CXL-1020 and SNP increased stroke volume without increasing heart rate. However, unlike SNP, CXL-1020 also showed significantly improved heart muscle contraction (inotropy) and relaxation (lusitropy). Moreover, study findings reported that the effects of CXL-1020 were independent from Beta-Adrenergic Receptor and ACE-inhibitor pathways. Compared to the inotrope dobutamine , CXL-1020 significantly reduced after-load, stroke work and energetic demand, demonstrating its unique, energetically favorable profile. The researchers conclude that CXL-1020, through its unique mechanism of action, improves heart function in a manner distinct from nitrovasodilators, and that its efficacy will not be reduced with either beta-blockers or ACE inhibitors, medicines commonly prescribed for patients with heart failure.
A Phase I/IIa First in Man Safety and Tolerability Study of a Novel HNO Donor, CXL-1020, in Patients with Stable Congestive Heart Failure. Monday, April 4, 2011; 9:30 a.m. – 12:30 p.m., Ernest N. Morial Convention Center, Hall F; Poster Board #42
The data presented in this poster demonstrates the safety and tolerability of the novel treatment, CXL-1020, in stable congestive heart failure (CHF) patients. In the double-blind, placebo controlled, randomized, dose escalation study, two cohorts of patients received four sequentially increasing four-hour infusions, at half-log dose increments between 0.1-30 microgram/kg/min with a randomly interspersed placebo. Patient safety was monitored throughout the study. Researchers also evaluated the plasma and urine pharmacokinetics (PK) during treatment and up to 24 hours post dosing. The results show that CXL-1020 was well tolerated at doses up to 10 microgram/kg/min with no significant change in heart rate or systolic blood pressure, no decrease in kidney function, and no increase in ventricular ectopy. The PK of CXL-1020 and its by-product were dose-proportional, and greater than 90 percent of the by-product was recovered unchanged in the urine within 24 hours post-dose. At the highest dose (30 microgram/kg/min), 33 percent of patients met a pre-specified criterion for termination of treatment due to a fall in systolic blood pressure of greater than or equal to 20 millimeters of mercury. No severe adverse events were observed.
Doug Cowart, Pharm D., FABCP, RAC, Cardioxyl’s Executive Vice President, Development and Regulatory Affairs, said, “These initial clinical results are consistent with our preclinical studies and support that CXL-1020 has a predictable pharmacokinetic profile, an acceptable safety profile and appears to be well tolerated by patients.”
Cardioxyl has developed a nitroxyl chemistry platform technology that serves as the foundation for the company's drug discovery efforts. In research published by Cardioxyl’s scientific founders from Johns Hopkins University, nitroxyl was shown to have positive vasodilatory and direct myocardial effects. CXL-1020, a proprietary nitroxyl donor, is Cardioxyl’s lead compound for the intravenous treatment of acute decompensated heart failure (ADHF). A prodrug, CXL-1020 once administered, chemically converts into an active nitroxyl (HNO) compound and an organic byproduct. In pre-clinical models of heart failure, CXL-1020 improves cardiovascular performance by enhancing the contractility (inotropy) and relaxation (lusitropy) of the failing heart and dilating the peripheral vasculature (vasodilation), without increasing heart rate or myocardial oxygen consumption. Cardioxyl completed a Phase I/IIa safety and dose-escalation study of CXL-1020 in stable chronic heart failure subjects and has announced initiation of a Phase IIa trial. Based on all pre-clinical studies to date, CXL-1020 is anticipated to improve the symptoms, hemodynamics and clinical status of patients with ADHF.
About Cardioxyl Pharmaceuticals
Cardioxyl Pharmaceuticals is a clinical-stage pharmaceutical company focused on the discovery and development of new classes of safe and effective therapeutic agents for the treatment of cardiovascular disease. Cardioxyl has developed industry-leading expertise in the chemistry, biology and clinical applications of nitroxyl (HNO) technology. The company's core HNO platform has generated several pre-clinical and clinical candidates, including the company's lead compound, CXL-1020, currently in clinical development for ADHF. Cardioxyl is a privately held company financed by life science venture investors, including the Aurora Funds and New Enterprise Associates.
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About Acute Decompensated Heart Failure (ADHF) & Current Treatment Options
ADHF is the leading diagnosis at the time of discharge from U.S. hospitals and the most common cause of hospitalization for patients over 65 years of age.i Well over $39 billion was spent in the U.S. in 2009 for the medical care of heart failure patients. ADHF is a deadly condition, with in-hospital mortality rates of two to six percent and six-month readmission rates as high as 30 to 60 percent. Episodes of ADHF are marked by a severe reduction of cardiac function that typically results in fluid accumulation in the lungs (pulmonary edema) and consequent severe shortness of breath. There were 1.1 million hospitalizations for acute heart failure in the U.S. in 2006. Among patients hospitalized with ADHF, the 30-day mortality rate is approximately 11 percent and the one-year mortality rate is 34 percent. These poor outcomes indicate the clear need for better therapies to treat this patient population.
Despite the severity of the condition, the treatment options available for patients with ADHF remain limited. Current first-line treatments target the removal of excess fluid (diuresis) and preload and afterload reduction (vasodilation). In order to improve the hemodynamic profile of the heart and increase cardiac contractility, a physician may also administer an intravenous inotropic agent such as dobutamine (beta-adrenergic agonist) or milrinone (PDE3-inhibitor). Administration of dobutamine or milrinone often requires very close monitoring in the hospital’s cardiac or intensive care unit setting due to the life-threatening safety risks associated with these drugs, including ventricular/atrial arrhythmias, hypotension, sudden cardiac death, and other potential adverse long term outcomes.[i],[ii]